Structural modifications toward improved lead-203/lead-212 peptide-based image-guided alpha-particle radiopharmaceutical therapies for neuroendocrine tumors.

PURPOSE: The lead-203 (203Pb)/lead-212 (212Pb) elementally identical radionuclide pair has gained significant interest in the field of image-guided targeted alpha-particle therapy for cancer. Emerging evidence suggests that 212Pb-labeled peptide-based radiopharmaceuticals targeting somatostatin receptor subtype 2 (SSTR2) may provide improved effectiveness compared to beta-particle-based therapies for neuroendocrine tumors (NETs). This study aims to improve the performance of SSTR2-targeted radionuclide imaging and therapy through structural modifications to Tyr3-octreotide (TOC)-based radiopharmaceuticals. METHODS: New SSTR2-targeted peptides were designed and synthesized with the goal of optimizing the incorporation of Pb isotopes through the use of a modified cyclization technique; the introduction of a Pb-specific chelator (PSC); and the insertion of polyethylene glycol (PEG) linkers. The binding affinity of the peptides and the cellular uptake of 203Pb-labeled peptides were evaluated using pancreatic AR42J (SSTR2+) tumor cells and the biodistribution and imaging of the 203Pb-labeled peptides were assessed in an AR42J tumor xenograft mouse model. A lead peptide was identified (i.e., PSC-PEG2-TOC), which was then further evaluated for efficacy in 212Pb therapy studies. RESULTS: The lead radiopeptide drug conjugate (RPDC) - [203Pb]Pb-PSC-PEG2-TOC - significantly improved the tumor-targeting properties, including receptor binding and tumor accumulation and retention as compared to [203Pb]Pb-DOTA0-Tyr3-octreotide (DOTATOC). Additionally, the modified RPDC exhibited faster renal clearance than the DOTATOC counterpart. These advantageous characteristics of [212Pb]Pb-PSC-PEG2-TOC resulted in a dose-dependent therapeutic effect with minimal signs of toxicity in the AR42J xenograft model. Fractionated administrations of 3.7 MBq [212Pb]Pb-PSC-PEG2-TOC over three doses further improved anti-tumor effectiveness, resulting in 80% survival (70% complete response) over 120 days in the mouse model. CONCLUSION: Structural modifications to chelator and linker compositions improved tumor targeting and pharmacokinetics (PK) of 203/212Pb peptide-based radiopharmaceuticals for NET theranostics. These findings suggest that PSC-PEG2-TOC is a promising candidate for Pb-based targeted radionuclide therapy for NETs and other types of cancers that express SSTR2.

Regional Myocardial Remodeling Characteristics Correlates With Cardiac Events in Sarcoidosis.

BACKGROUND: The poor prognosis of cardiac sarcoidosis (CS) underscores the need for risk stratification. PURPOSE: To investigate the prognostic significance of ventricular/myocardial remodeling features in sarcoidosis. STUDY TYPE: Retrospective. POPULATION: In all, 132 biopsy-proven sarcoidosis patients imaged from 2008 to 2018. The primary endpoint was a composite of cardiac mortality, new onset arrhythmias, hospitalization for heart failure, and device implantation. FIELD STRENGTH/SEQUENCE: No field strength or sequence restrictions. ASSESSMENT: Global and regional ventricular/myocardial remodeling features were assessed by standard volumetric measurements and automated function imaging postprocessing analysis. STATISTICAL TESTS: Student's t-test or Mann-Whitney test (chi2 test or Fisher's exact test for categorical variables) were used for comparisons. Cox-proportional hazards regression model, univariate /multivariate analyses, and receiver operating characteristic were performed to relate clinical/lab data, imaging parameters to the endpoints. RESULTS: Over a median follow-up of 40.7 (interquartile range 18.8-60.5) months, 41 (31.1%) patients developed adverse cardiac events. Abnormal left ventricular (LV) geometric remodeling alterations (measured by LV mass index and relative wall thickness) occurred 3.66-fold more frequently in patients with endpoints than patients without. The ratio of patients with endpoints increased as ventricular remodeling phenotype progressed. In patients with endpoints, regional myocardial wall thickness (RMWT) was significantly (P = 0.022) increased in six clustered LV segments located in the middle interventricular septum and basal/middle anterolateral walls. In all of the abnormal ventricular remodeling stages, patients with endpoints constantly had higher mean RMWT than those without. Among clinical, electrocardiographic, and imaging parameters, LV mass index (hazard ratio [HR] 1.010 95% confidence interval [CI] 1.002-1.018, P = 0.017) and mean RMWT (HR 3.482 95% CI 1.679-7.223, P = 0.001) were independently associated with endpoints. Sarcoidosis patients without this RMWT distribution pattern were significantly (P < 0.001) more likely to be free of the occurrence of subsequent cardiac events. DATA CONCLUSION: Regional myocardial remodeling characteristics are associated with subsequent adverse cardiac events in sarcoidosis. LEVEL OF EVIDENCE: 3 TECHNICAL EFFICACY STAGE: 2 J. Magn. Reson. Imaging 2020;52:499-509.

Polyazamacrocycle Ligands Facilitate 89Zr Radiochemistry and Yield 89Zr Complexes with Remarkable Stability.

Over the last three decades, the chemistry of zirconium has facilitated antibody development and the clinical management of disease in the precision medicine era. Scientists have harnessed its reactivity, coordination chemistry, and nuclear chemistry to develop antibody-based radiopharmaceuticals incorporating zirconium-89 (89Zr: t1/2 = 78.4 h, ß+: 22.8%, Eß+max = 901 keV; EC: 77%, Eγ = 909 keV) to improve disease detection, identify patients for individualized therapeutic interventions. and monitor their response to those interventions. However, release of the 89Zr4+ ion from the radiopharmaceutical remains a concern, since it may confound the interpretation of clinical imaging data, negatively affect dosimetric calculations, and hinder treatment planning. In this report, we relate our novel observations involving the use of polyazamacrocycles as zirconium-89 chelators. We describe the synthesis and complete characterization of zirconium 2,2',2″,2‴-(1,4,7,10-tetraazacyclotridecane-1,4,7,10-tetrayl)tetraacetic acid (Zr-TRITA), zirconium 3,6,9,15-Tetraazabicyclo[9.3.1] pentadeca-1(15),11,13-triene-3,6,9-triacetic acid (Zr-PCTA), and zirconium 2,2',2″-(1,4,7-triazacyclononane-1,4,7-triyl)triacetic acid (Zr-NOTA). In addition, we elucidate the solid-state structure of each complex using single-crystal X-ray diffraction analysis. Finally, we found that [89Zr]Zr-PCTA and [89Zr]Zr-NOTA demonstrate excellent stability in vitro and in vivo and provide a rationale for these observations. These innovative findings have the potential to guide the development of safer and more robust immuno-PET agents to improve precision medicine applications.

Comparison of T1Rho MRI, Glucose Metabolism, and Amyloid Burden Across the Cognitive Spectrum: A Pilot Study.

OBJECTIVE: The pathological cascades associated with the development of Alzheimer's disease (AD) have a common element: acidosis. T1rho MRI is a pH-sensitive measure, with higher values associated with greater neuropathological burden. The authors investigated the relationship between T1rho imaging and AD-associated pathologies as determined by available diagnostic imaging techniques. METHODS: Twenty-seven participants (men, N=13, women, N=14; ages 55-90) across the cognitive spectrum (healthy control subjects [HCs] with normal cognition, N=17; participants with mild cognitive impairment [MCI], N=7; participants with mild AD, N=3) underwent neuropsychological testing, MRI (T1-weighted and T1rho [spin-lattice relaxation time in the rotating frame]), and positron emission tomography imaging ([11C]Pittsburg compound B for amyloid burden [N=26] and [18F]fluorodeoxyglucose for cerebral glucose metabolism [N=12]). The relationships between global T1rho values and neuropsychological, demographic, and imaging measures were explored. RESULTS: Global mean and median T1rho were positively associated with age. After controlling for age, higher global T1rho was associated with poorer cognitive function, poorer memory function (immediate and delayed memory scores), higher amyloid burden, and more abnormal cerebral glucose metabolism. Regional T1rho values, when controlling for age, significantly differed between HCs and participants with MCI or AD in select frontal, cingulate, and parietal regions. CONCLUSIONS: Higher T1rho values were associated with greater cognitive impairment and pathological burden. T1rho, a biomarker that varies according to a feature common to each cascade rather than one that is unique to a particular pathology, has the potential to serve as a metric of neuropathology, theoretically providing a measure for assessing pathological status and for monitoring the neurodegeneration trajectory.

Preliminary Investigation of Cerebral Blood Flow and Amyloid Burden in Veterans With and Without Combat-Related Traumatic Brain Injury.

This study aimed to examine global and regional cerebral blood flow and amyloid burden in combat veterans with and without traumatic brain injury (TBI). Cerebral blood flow (in milliliters per minute per 100 mL) was measured by quantitative [(15)O]water, and amyloid burden was measured by [(11)C]PIB imaging. Mean global cerebral blood flow was significantly lower in veterans with TBI compared with non-TBI veterans. There were essentially no differences between groups for globally normalized regional cerebral blood flow. Amyloid burden did not differ between TBI and non-TBI veterans. Veterans who have suffered a TBI have significantly lower cerebral blood flow than non-TBI controls but did not manifest increased levels of amyloid, globally or regionally.

Dependency of cardiac rubidium-82 imaging quantitative measures on age, gender, vascular territory, and software in a cardiovascular normal population.

OBJECTIVES: Recent technological improvements to PET imaging equipment combined with the availability of software optimized to calculate regional myocardial blood flow (MBF) and myocardial flow reserve (MFR) create a paradigm shifting opportunity to provide new clinically relevant quantitative information to cardiologists. However, clinical interpretation of the MBF and MFR is entirely dependent upon knowledge of MBF and MFR values in normal populations and subpopulations. This work reports Rb-82-based MBF and MFR measurements for a series of 49 verified cardiovascularly normal subjects as a preliminary baseline for future clinical studies. METHODS: Forty-nine subjects (24F/25M, ages 41-69) with low probability for coronary artery disease and with normal exercise stress test were included. These subjects underwent rest/dipyridamole stress Rb-82 myocardial perfusion imaging using standard clinical techniques (40 mCi injection, 6-minute acquisition) using a Siemens Biograph 40 PET/CT scanner with high count rate detector option. List mode data was rehistogrammed into 26 dynamic frames (12 × 5 seconds, 6 × 10 seconds, 4 × 20 seconds, 4 × 40 seconds). Cardiac images were processed, and MBF and MFR calculated using Siemens syngo MBF, PMOD, and FlowQuant software using a single compartment Rb-82 model. RESULTS: Global myocardial blood flow under pharmacological stress for the 24 females as measured by PMOD, syngo MBF, and FlowQuant were 3.10 ± 0.72, 2.80 ± 0.66, and 2.60 ± 0.63 mL·minute(-1)·g(-1), and for the 25 males was 2.60 ± 0.84, 2.33 ± 0.75, 2.15 ± 0.62 mL·minute(-1)·g(-1), respectively. Rest flows for PMOD, syngo MBF, and FlowQuant averaged 1.32 ± 0.42, 1.20 ± 0.33, and 1.06 ± 0.38 mL·minute(-1)·g(-1) for the female subjects, and 1.12 ± 0.29, 0.90 ± 0.26, and 0.85 ± 0.24 mL·minute(-1)·g(-1) for the males. Myocardial flow reserves for PMOD, syngo MBF, and FlowQuant for the female normals were calculated to be 2.50 ± 0.80, 2.53 ± 0.67, 2.71 ± 0.90, and 2.50 ± 1.19, 2.85 ± 1.19, 2.94 ± 1.31 mL·minute(-1)·g(-1) for males. CONCLUSION: Quantitative normal MBF and MFR values averaged for age and sex have been compiled for three commercial pharmacokinetic software packages. The current collection of data consisting of 49 subjects resulted in several statistically significant conclusions that support the need for a software specific, age, and sex-matched database to aid in interpretation of quantitative clinical myocardial perfusion studies.

Frontal hypometabolism in elderly breast cancer survivors determined by [(18)F]fluorodeoxyglucose (FDG) positron emission tomography (PET): a pilot study.

PURPOSE: The term "chemobrain" is sometimes used to denote deficits in neuropsychological functioning that may occur as a result of cancer treatment. As breast cancer survivors now commonly reach late life, it is not known whether previous exposure to chemotherapy may affect long-term risk for cognitive impairment. To help address this concern, this study tested whether successfully surviving chemotherapy earlier in life was associated with later differences in brain metabolic function as an older adult compared to controls. This question was examined using positron emission tomography measures of brain glucose metabolism in elderly women cancer survivors. METHODS: Breast cancer survivors (N = 10), currently free of recurrent cancer and without a diagnosis of a cognitive disorder, were compared to matched healthy controls (N = 10). All subjects were imaged at rest with [(18)F]fluorodeoxyglucose. Images were analyzed semi-quantitatively using the Alzheimer's Discrimination Tool and a volume of interest-based approach derived from co-registered magnetic resonance imaging. RESULTS: Relative [(18)F]fluorodeoxyglucose uptake (normalized to global) was significantly lower in the survivors compared with control subjects in bilateral orbital frontal regions, consistent with differences between the groups in cognition and executive function (i.e., Trail Making Test, Part B and mini-mental state examination) and despite no significant differences with respect to age, education, intelligence, or working memory. None of the survivors and only one control manifested a global positron emission tomography score consistent with an Alzheimer's disease metabolic pattern. CONCLUSION: Breast cancer survivors treated with chemotherapy may manifest long-term changes in brain glucose metabolism indicative of subtle frontal hypometabolism, a finding consistent with results from neuropsychological testing and other imaging modalities.

Limitations of somatostatin scintigraphy in primary small bowel neuroendocrine tumors.

BACKGROUND: Somatostatin receptor scintigraphy (SRS; octreoscan) is used in neuroendocrine tumors to locate the primary tumor site and delineate the extent of disease. SRS has decreased sensitivity for small bowel neuroendocrine tumors (SBNETs). The reasons for SRS nonlocalization are not clear. We sought to determine factors that correlate with successful primary tumor localization by SRS in patients with resected SBNETs, and also identify factors that confound interpretation of SRS reports. METHODS: Records of patients with resected SBNETs were reviewed for SRS results, tumor size, multifocality, N, and M status. Somatostatin receptor 2 (SSTR2) expression was analyzed in resected tumors by quantitative polymerase chain reaction. SRS reports were reviewed and categorized as localizing the primary tumor or not. A nuclear medicine physician independently reviewed available images. RESULTS: Of 37 patients with preoperative SRS, the primary tumor was localized in 37%. Of all the factors tested, only small tumor size correlated significantly with SRS nonlocalization. Overexpression of SSTR2 was not significantly different between tumors that were or were not localized by SRS, regardless of tumor size. There were three instances where the SRS report did not agree with the nuclear medicine physician's interpretation as to whether SRS localized the primary tumor. In each case, uptake in mesenteric nodes was a confounding factor. CONCLUSIONS: SBNETs <2 cm are most likely to be missed by SRS. SSTR2 expression did not correlate with SRS nonlocalization of the primary tumor. Uptake in mesenteric nodes may help indicate an SBNET primary but can also interfere with its visualization within the small bowel.

Spatial mapping of functional pelvic bone marrow using FLT PET.

The purpose of this study was to determine the ability of regions identified with bony landmarks on CT imaging to accurately represent active bone marrow when compared to FLT PET imaging. These surrogate regions could then be used to create a bone marrow sparing radiation therapy plan when FLT PET imaging is not available. Whole body (WB) FLT PET images were obtained of 18 subjects prior to chemoradiation therapy. The FLT image of each subject was registered to a CT image acquired for that subject to obtain anatomic information of the pelvis. Seventeen regions were identified based on features of the pelvic bones, sacrum, and femoral heads. The probability of FLT uptake being located in each of 17 different CT-based regions of the bony pelvis was calculated using Tukey's multiple comparison test. Statistical analysis of FLT uptake in the pelvis indicated four distinct groups within the 17 regions that had similar levels of activity. Regions located in the central part of the pelvis, including the superior part of the sacrum, the inner halves of the iliac crests, and the L5 vertebral body, had greater FLT uptake than those in the peripheral regions (p-value < 0.05). We have developed a method to use CT-defined pelvic bone regions to represent FLT PET-identified functional bone marrow. Individual regions that have a statistically significant probability of containing functional bone marrow can be used as avoidance regions to reduce radiation dose to functional bone marrow in radiation therapy planning. However, because likely active bone marrow regions and pelvic targets typically overlap, patient-specific spatial detail may be advantageous in IMRT planning scenarios and may best be provided using FLT PET imaging.

Auranofin Inhibition of Thioredoxin Reductase Sensitizes Lung Neuroendocrine Tumor Cells (NETs) and Small Cell Lung Cancer (SCLC) Cells to Sorafenib as well as Inhibiting SCLC Xenograft Growth.

Thioredoxin Reductase (TrxR) is a key enzyme in hydroperoxide detoxification through peroxiredoxin enzymes and in thiol-mediated redox regulation of cell signaling. Because cancer cells produce increased steady-state levels of reactive oxygen species (ROS; i.e., superoxide and hydrogen peroxide), TrxR is currently being targeted in clinical trials using the anti-rheumatic drug, auranofin (AF). AF treatment decreased TrxR activity and clonogenic survival in small cell lung cancer (SCLC) cell lines (DMS273 and DMS53) as well as the lung atypical (neuroendocrine tumor) NET cell line H727. AF treatment also significantly sensitized DMS273 and H727 cell lines in vitro to sorafenib, a multi-kinase inhibitor that was shown to decrease intracellular glutathione. The pharmacokinetic and pharmacodynamic properties of AF treatment in a mouse SCLC xenograft model was examined to maximize inhibition of TrxR activity without causing toxicity. AF was administered intraperitoneally at 2 mg/kg or 4 mg/kg (IP) once (QD) or twice daily (BID) for 1 to 5 days in mice with DMS273 xenografts. Plasma levels of AF were 10-20 µM (determined by mass spectrometry of gold) and the optimal inhibition of TrxR (50 %) was obtained at 4 mg/kg once daily, with no effect on glutathione peroxidase 1 activity. When this daily AF treatment was extended for 14 days a significant prolongation of median survival from 19 to 23 days (p=0.04, N=30 controls, 28 AF) was observed without causing changes in animal bodyweight, CBCs, bone marrow toxicity, blood urea nitrogen, or creatinine. These results show that AF is an effective inhibitor of TrxR both in vitro and in vivo in SCLC, capable of sensitizing NETs and SCLC to sorafenib, and supports the hypothesis that AF could be used as an adjuvant therapy with agents known to induce disruptions in thiol metabolism to enhance therapeutic efficacy.

Chemokine Receptor CXCR4 Radioligand Targeted Therapy Using 177Lutetium-pentixather for Pulmonary Neuroendocrine Cancers.

Intermediate to high-grade lung neuroendocrine tumors (NETs; i.e., atypical carcinoid tumors) and neuroendocrine carcinomas (NECs) are currently difficult to cure. These tumors were found to express the CXCR4 G-protein coupled receptor that can be targeted with radioligands. PCR and flow cytometric analysis of lung NET and NEC cell lines using an anti-CXCR4 antibody demonstrated that all cell lines tested expressed CXCR4. PET/CT imaging with 68Galium-pentixafor in mouse xenografts of NETs and NECs verified tumor targeting that was blocked by a CXCR4 agonist. Clonogenic survival analysis demonstrated a more than additive enhancement of killing when 1 µM auranofin (a thioredoxin reductase inhibitor) was used as a radiosensitizer in combination with 177Lu-pentixather (10 µCi). DMS273 small cell lung cancer xenografts in female nude mice treated with 25 µCi/g 177Lu-pentixather induced inhibition of tumor growth and resulted in an increase in overall survival without causing unacceptable normal tissue toxicities. Immunohistochemical staining of 95 retrospective human samples (containing 90 small cell lung carcinomas) demonstrated 84% CXCR4 positivity. In a multivariable analysis of this cohort that included age, gender, stage, primary site, SSTR2 status, and CXCR4 status, Cox regression models determined that only distant metastasis at presentation (P < 0.01) and a CXCR4 H-score >30 (P = 0.04) were significantly associated with reduced survival. Prospective clinical testing of patient tumors identified CXCR4-positivity in 76% of 21 NECs, 67% of 15 lung NETs (including 8 of 10 atypical carcinoids), and 0% of 25 non-lung NETs (including 5 NETS G3s). These data support the hypothesis that CXCR4-targeted theranostics can be utilized effectively for select NETs and NECs.

The value of preoperative imaging in small bowel neuroendocrine tumors.

BACKGROUND: Neuroendocrine tumors of the small bowel (SBNETs) are a rare but important subgroup of malignancies. Since 30 % of SBNETs present with metastatic disease, often with an occult primary, preoperative imaging is critical for determining who will benefit most from abdominal exploration. We set out to evaluate the usefulness of the two most commonly performed imaging modalities in predicting the extent of disease found at exploration in patients with SBNETs. METHODS: A retrospective chart review was performed on patients with SBNETs resected at 1 institution. Data from preoperative computed tomography (CT) scans were reviewed to determine whether the primary tumor, nodal, or liver metastases were seen, then compared with intraoperative findings. Results of preoperative somatostatin receptor scintigraphy (SRS) were similarly examined. RESULTS: A total of 62 patients with SBNETs were included. Of these patients, 42 of 62 (68 %) had distant metastases and 48 of 62 (77 %) had nodal metastases at exploration. A total of 56 patients had preoperative CT scans and 47 had SRS. Using CT, a primary tumor was localized to the small bowel in 27 of 56 (48 %) and nodal metastases seen in 33 of 56 (79 %) of cases. SRS found intra-abdominal uptake in 35 of 47 cases (74 %). CONCLUSIONS: CT and SRS are complementary in making the diagnosis of SBNET, with CT giving more precise anatomical detail, while SRS helps to confirm that lesions are NETs and is useful for identifying occult extrahepatic sites of metastatic disease. However, 10-15 % of SBNETs were not identified by either test preoperatively, and therefore surgical exploration still plays an important role in making the diagnosis in these patients.

PET/CT Imaging in Treatment Planning and Surveillance of Sinonasal Neoplasms.

Sinonasal cancers are uncommon malignancies with a generally unfavorable prognosis, often presenting at an advanced stage. Their high rate of recurrence supports close imaging surveillance and the utilization of functional imaging techniques. Whole-body 18F-FDG PET/CT has very high sensitivity for the diagnosis of sinonasal malignancies and can also be used as a "metabolic biopsy" in the characterization of some of the more common subgroups of these tumors, though due to overlap in uptake, histological confirmation is still needed. For certain tumor types, radiotracers, such as 11C-choline, and radiolabeled somatostatin analogs, including 68Ga-DOTATATE/DOTATOC, have proven useful in treatment planning and surveillance. Although serial scans for posttreatment surveillance allow the detection of subclinical lesions, the optimal schedule and efficacy in terms of survival are yet to be determined. Pitfalls of 18F-FDG, such as post-surgical and post-radiotherapy crusting and inflammation, may cause false-positive hypermetabolism in the absence of relapse.

American Thoracic Society documents: an official American Thoracic Society/Society of Thoracic Radiology Clinical Practice Guideline--Evaluation of Suspected Pulmonary Embolism in Pregnancy.

BACKGROUND: Pulmonary embolism (PE) is a leading cause of maternal mortality in the developed world. Along with appropriate prophylaxis and therapy, prevention of death from PE in pregnancy requires a high index of clinical suspicion followed by a timely and accurate diagnostic approach. METHODS: To provide guidance on this important health issue, a multidisciplinary panel of major medical stakeholders was convened to develop evidence-based guidelines for evaluation of suspected pulmonary embolism in pregnancy using the Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) system. In formulation of the recommended diagnostic algorithm, the important outcomes were defined to be diagnostic accuracy and diagnostic yield; the panel placed a high value on minimizing cumulative radiation dose when determining the recommended sequence of tests. RESULTS: Overall, the quality of the underlying evidence for all recommendations was rated as very low or low with some of the evidence considered for recommendations extrapolated from studies of the general population. Despite the low quality evidence, strong recommendations were made for three specific scenarios: performance of chest radiography (CXR) as the first radiation-associated procedure; use of lung scintigraphy as the preferred test in the setting of a normal CXR; and performance of computed-tomographic pulmonary angiography (CTPA) rather than digital subtraction angiography (DSA) in a pregnant woman with a nondiagnostic ventilation-perfusion (V/Q) result. DISCUSSION: The recommendations presented in this guideline are based upon the currently available evidence; availability of new clinical research data and development and dissemination of new technologies will necessitate a revision and update.

An official American Thoracic Society/Society of Thoracic Radiology clinical practice guideline: evaluation of suspected pulmonary embolism in pregnancy.

BACKGROUND: Pulmonary embolism (PE) is a leading cause of maternal mortality in the developed world. Along with appropriate prophylaxis and therapy, prevention of death from PE in pregnancy requires a high index of clinical suspicion followed by a timely and accurate diagnostic approach. METHODS: To provide guidance on this important health issue, a multidisciplinary panel of major medical stakeholders was convened to develop evidence-based guidelines for evaluation of suspected pulmonary embolism in pregnancy using the Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) system. In formulation of the recommended diagnostic algorithm, the important outcomes were defined to be diagnostic accuracy and diagnostic yield; the panel placed a high value on minimizing cumulative radiation dose when determining the recommended sequence of tests. RESULTS: Overall, the quality of the underlying evidence for all recommendations was rated as very low or low, with some of the evidence considered for recommendations extrapolated from studies of the general population. Despite the low-quality evidence, strong recommendations were made for three specific scenarios: performance of chest radiography (CXR) as the first radiation-associated procedure; use of lung scintigraphy as the preferred test in the setting of a normal CXR; and performance of computed-tomographic pulmonary angiography (CTPA) rather than digital subtraction angiography (DSA) in a pregnant woman with a nondiagnostic ventilation-perfusion (V/Q) result. DISCUSSION: The recommendations presented in this guideline are based upon the currently available evidence; availability of new clinical research data and development and dissemination of new technologies will necessitate a revision and update.

The Impact of Radiopharmaceutical Therapy on Renal Function.

Radiopharmaceuticals used for cancer therapy are highly selective, designed to kill malignant cells and spare healthy tissues. Side effect rates are generally less than other treatments, but it is still the utmost concern to minimize normal organ toxicity and maximize radiation dose to the target lesions in applying radiopharmaceutical therapies (RPTs). Most commonly affected normal organs include bone marrow, kidneys and liver. The impact of RPTs to renal function is generally considered low. Peptide receptor radionuclide therapy (PRRT) using somatostatin radiopharmaceuticals, particularly 90Y-DOTATOC, has the potential to induce nephrotoxicity. This is because PRRT radiopharmaceuticals are primarily cleared thorough glomerular filtration and reabsorption/retainment of them at the renal proximal tubules exposes kidneys to additional radiation. Amino acid co-infusion is the standard regimen for competitive inhibition of tubular reabsorption of PRRT radiopharmaceuticals to mitigate nephrotoxicity. Other measures to protect renal function include hydration, use of plasma expander or radioprotectant, personalized renal dosimetry to limit renal radiation dose and close monitoring of renal function. Limited data suggest alpha emitter PRRT radiopharmaceuticals have less impact on kidney function compared to beta emitter PRRT, but more studies are needed for long term renal toxicity. 131I-MIBG is primarily excreted unchanged thorough the kidneys but renal absorbed dose is low and potential toxicities to the bone marrow and lungs are the most significant clinical concerns. Other RPTs that are not mainly cleared through kidneys such as 223Ra or radioimmunotherapy have no concern for kidney toxicity.

Radiopharmaceuticals for Neuroendocrine Tumors.

Neuroendocrine tumors (NETs) are a heterogeneous group of tumors that originate in endocrine tissues throughout the body. Peptide receptor radionuclide therapy (PRRT) has emerged as a promising therapeutic option for patients with locally advanced and/or metastatic disease refractory to standard of care treatment. The landmark international phase III NETTER-1 trial led to the approval of 177Lu-DOTATATE (Lutathera) in the treatment of somatostatin receptor-positive gastroenteropancreatic NETs. Similarly, data from the multicenter, phase II Study IB12B led to the approval of meta-[131I]Iodo-Benzyl-Guanidine (I31I-MIBG) for treatment of iobenguane scan-positive, unresectable, locally advanced or metastatic pheochromocytoma or paraganglioma. With the clinical approval of these novel radiopharmaceuticals for managing select patients with NETs, additional studies are needed to refine patient selection, predict and assess therapy response, and optimize radiopharmaceutical delivery and clinical outcomes.

Potential for Increasing Uptake of Radiolabeled 68Ga-DOTATOC and 123I-MIBG in Patients with Midgut Neuroendocrine Tumors Using a Histone Deacetylase Inhibitor Vorinostat.

Background: Histone deacetylase (HDAC) inhibitors have been shown in preclinical studies to upregulate norepinephrine transporters in neuroblastoma and pheochromocytoma, and somatostatin receptors in pulmonary carcinoid, small cell lung cancer, and pancreatic neuroendocrine malignancies. This pilot imaging study in humans focuses on midgut neuroendocrine carcinoma metastatic to the liver, evaluating the effect of pretreatment with the HDAC inhibitor vorinostat on uptake of 123I-MIBG and 68Ga-DOTATOC. Materials and Methods: Multiple midgut neuroendocrine liver metastases in clinically stable subjects were imaged with 123I-MIBG and 68Ga-DOTATOC before and after a 4-d course of vorinostat. Scans were performed with strict attention to detail and timed about 1 month apart occurring just before monthly long-acting octreotide administrations. Uptake changes in tumor and normal liver parenchyma were assessed on positron emission computed tomography (PET/CT) with standardized uptake values and on single photon emission computed tomography (SPECT) with qualitative ratio images. Results: The experimental units were metastatic liver lesions within patients (n = 50). There was no significant difference in administered activity or uptake time between pairs of scans for either radiotracer. Statistically significant increase in maximum standardized uptake values (SUVmax) averaged over all lesions was noted on the 68Ga-DOTATOC PET scans (+11%, p < 0.01). SUVmax in normal liver showed no significant change (p = 0.12). There was no qualitative change in uptake of 123I-MIBG after vorinostat. Conclusions: In this pilot imaging study in patients with midgut neuroendocrine liver metastases, a short course of the HDAC inhibitor vorinostat induced a statistically significant increase in SUVmax on 68Ga-DOTATOC PET/computed tomography (CT) imaging in some hepatic neuroendocrine tumor metastases. There was no significant effect of vorinostat on tumor uptake of 123I-MIBG on SPECT/CT imaging. Given the pilot nature of this trial, the findings merit further investigation with a more rigorous protocol evaluating longer pretreatment and different dosages of vorinostat or other HDAC inhibitors, as well as effects on the therapeutic capability of 177Lu- or 90Y-somatostatin analogs.

Multiparametric magnetic resonance imaging and positron emission tomography findings in neurodegenerative diseases: Current status and future directions.

Neurodegenerative diseases (NDDs) are characterized by progressive neuronal loss, leading to dementia and movement disorders. NDDs broadly include Alzheimer's disease, frontotemporal lobar degeneration, parkinsonian syndromes, and prion diseases. There is an ever-increasing prevalence of mild cognitive impairment and dementia, with an accompanying immense economic impact, prompting efforts aimed at early identification and effective interventions. Neuroimaging is an essential tool for the early diagnosis of NDDs in both clinical and research settings. Structural, functional, and metabolic imaging modalities, including magnetic resonance imaging (MRI) and positron emission tomography (PET), are widely available. They show encouraging results for diagnosis, monitoring, and treatment response evaluation. The current review focuses on the complementary role of various imaging modalities in relation to NDDs, the qualitative and quantitative utility of newer MRI techniques, novel radiopharmaceuticals, and integrated PET/MRI in the setting of NDDs.

A Framework for Patient-Centered Pathways of Care for Radiopharmaceutical Therapy: An ASTRO Consensus Document.

Radiopharmaceutical therapy (RPT) is an area of projected growth and importance with several agents in clinical use, new agents in late-phase clinical trials, and many others under testing and development. This article proposes a framework for developing pathways of care that can be broadly applied to all RPTs, representing the current status of RPT. It suggests foundational elements for many pathways of care for patients with cancer and concludes with areas in active development and the future horizon for RPT treatment centers. Developing a framework for patient-centered pathways of care is a critical step in establishing RPT as standard therapy for patients with a diverse spectrum of cancers. This expected increase in RPT treatment options will affect a much larger population of patients with complex cancer. It will also require enhanced coordination and collaboration among appropriately qualified personnel with diverse expertise in image acquisition, image interpretation, quantitative imaging, dosimetry calculation, radiation quality assurance and safety as well as oncology care and RPT-induced sequelae and response assessment. The essential role of this evolving RPT care team within multidisciplinary oncology care is a cornerstone of this framework for a patient-centered pathway of care for RPT. Given the status of current RPT practice and the horizon for future applications, this patient-centered pathway of care guidance is timely and should help inform future clinical RPT practice paradigms. A task force was recruited from the Theranostic Working Group of the American Society for Radiation Oncology (ASTRO) in May 2019 with equal representation from the nuclear medicine community. The task force expanded on a framework that was originally conceived by the Working Group for patient-centered care. This framework was developed to incorporate the strengths of both radiation oncologists and nuclear medicine physicians. The manuscript was then developed by the task force and posted on the ASTRO website for a 6-week public comment period ending in July 2020. Comments were adjudicated, and the draft was sent to external organizations for potential endorsement. This document was sent to the ASTRO Board of Directors in October 2020 for approval.